This invention relates to 3-desoxy-20-desmethyl-20-cyclopropyl vitamin D3 analog esters and methods for producing and using the same.
Osteoporosis is the most common form of metabolic bone disease and may be considered the symptomatic, fracture stage of bone loss (osteopenia). Although osteoporosis may occur secondary to a number of underlying diseases, 90% of all cases appear to be idiopathic. Postmenopausal women are at risk for idiopathic osteoporosis (postmenopausal or Type I osteoporosis); another particularly high risk group for idiopathic osteoporosis is the elderly of either sex (senile or Type II osteoporosis). Osteoporosis has also been related to corticosteroid use, immobilization or extended bed rest, alcoholism, diabetes, gonadotoxic chemo-therapy, hyperprolactinemia, anorexia nervosa, primary and secondary amenorrhea, transplant immunosuppression, and oophorectomy. Postmenopausal osteoporosis is characterized by fractures of the spine, while femoral neck fractures are the dominant features of senile osteoporosis.
The mechanism by which bone is lost in osteoporotics is believed to involve an imbalance in the process by which the skeleton renews itself. This process has been termed bone remodeling. It occurs in a series of discrete pockets of activity. These pockets appear spontaneously within the bone matrix on a given bone surface; as a site of bone resorption. Osteoclasts (bone dissolving or resorbing cells) are responsible for the resorption of a portion of bone of generally constant dimension. This resorption process is followed by the appearance of osteoblasts (bone forming cells) which then refill with new bone the cavity left by the osteoclasts.
In a healthy adult subject, osteoclasts and osteoblasts function so that bone formation and bone resorption are in balance. However, in osteoporotics an imbalance in the bone remodeling process develops which results in bone being replaced at a slower rate than it is being lost. Although this imbalance occurs to some extent in most individuals as they age, it is much more severe and occurs at a younger age in postmenopausal osteoporotics, following oophorectomy, or in iatrogenic situations such as those resulting from corticosteroid therapy or the immunosuppression practiced in organ transplantation.
Various approaches have been suggested for increasing bone mass in humans afflicted with osteoporosis, including administration of androgens, fluoride salts, and parathyroid hormone and modified versions of parathyroid hormone. It has also been suggested that bisphosphonates, calcitonin, calcium, 1,25-dihydroxy vitamin D3 and some of its analogs, and/or estrogens, alone or in combination, may be useful for preserving existing bone mass.
Vitamin D3 is a critical element in the metabolism of calcium, promoting intestinal absorption of calcium and phosphorus, maintaining adequate serum levels of calcium and phosphorus, and stimulating flux of calcium into and out of bone. Vitamin D3 is hydroxylated in vivo, with the resulting 1xcex1,25-dihydroxy metabolite being the active material. Animal studies with 1,25-(OH)2 vitamin D3 have suggested bone anabolic activity. Aerssens et al. in Calcif Tissue Int, 55:443-450 (1994) reported upon the effect of 1xcex1-hydroxy Vitamin D3 on bone strength and composition in growing rats with and without corticosteroid treatment. However, human usage is restricted to antiresorption due to the poor therapeutic ratio (hypercalciuria and hypercalcemia as well as nephrotoxicity).
Dechant and Goa, in xe2x80x9cCalcitriol. A review of its use in the treatment of postmenopausal osteoporosis and its potential in corticosteroid-induced osteoporosis,xe2x80x9d Drugs Aging [NEW ZEALAND 5 (4): 300-17 (1994)], reported that 1,25-dihydroxyvitamin D3 (calcitriol) has shown efficacy in the treatment of postmenopausal osteoporosis (and promise in corticosteroid-induced osteoporosis) based upon a clinical trial in 622 women with postmenopausal osteoporosis. Patients with mild to moderate disease (but not those with more severe disease) who received calcitriol (0.25 microgram twice daily) had a significant 3-fold lower rate of new vertebral fractures after 3 years of treatment compared with patients receiving elemental calcium 1000 mg/day. In patients commencing long term treatment with prednisone or prednisolone, calcitriol 0.5 to 1.0 micrograms/day plus calcium 1000 mg/day, administered with or without intranasal calcitonin 400 IU/day, prevented steroid-induced bone loss. Overall, calcitriol was well tolerated. At recommended dosages hypercalcaemia was infrequent and mild, generally responding to reductions in calcium intake and/or calcitriol dosage. However, the narrow therapeutic window of calcitriol required that its use be adequately supervised, with periodic monitoring of serum calcium and creatinine levels. This study clearly identifies the key limitation of calcitriol therapy as the close proximity of therapeutic and toxic doses.
Certain 3-desoxy-20-cyclopropyl vitamin D3 analogs are disclosed as inhibiting cellular proliferation in vitro in prostate cancer lines (xe2x80x9c20-Cyclopropyl-Cholecalciferol Vitamin D3 Analogs,xe2x80x9d M. Koike et. al., Anticancer Research, 19:1689-1698 (1999))
Secondary hyperparathyroidism is a common finding in patients with chronic renal failure. It is established that the reduction of renal 1,25(OH)2 vitamin D3 (calcitriol) synthesis is one of the principal mechanisms leading to the secondary hyperparathyroidism in these patients and it has been shown that calcitriol possesses direct suppressive action on PTH synthesis. Therefore, administration of calcitriol has been recommended for the treatment of secondary hyperparathyroidism in these patients. However, as described above, calcitriol has potent hypercalcemic effects giving it a narrow therapeutic window which limits its usage, especially at high doses. It would therefore be desirable to have an alternative means of treating hyperparathyroidism without incurring these undesirable hypercalcemic effects.
While a variety of compounds are available for treating these and other diseases, many of these compounds have undesirable side-effects and/or are relatively unstable, i.e., have short storage period. Therefore, there is a continuing needs for other compounds which are useful in treating these diseases.
One aspect of the present invention provides a 3-desoxy vitamin D3 analog ester of the formula: 
or a salt thereof, and methods for using and producing the same, where
dotted line is optionally a double bond;
L is a linker selected from the group consisting of:
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94, and
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
each of R2 and R3 is independently alkyl or haloalkyl; or R2 and R3 and together with the carbon atom to which they are attached to form a cycloalkyl; and
each of R1 and R4 is independently hydrogen, alkyl, acyl group or other hydroxy protecting group,
provided at least one of R1 and R4 is an acyl group.
xe2x80x9cAcetatexe2x80x9d or xe2x80x9cAcxe2x80x9d are used interchangeably herein and refer to a moiety of the formula xe2x80x94C(xe2x95x90O)CH3.
xe2x80x9cAcylxe2x80x9d refers to a moiety of the formula xe2x80x94C(O)Rxe2x80x2, where Rxe2x80x2 is alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
xe2x80x9cAlkylxe2x80x9d means a linear fully-saturated hydrocarbon moiety having one to six, preferably one to four, carbon atoms or a branched fully saturated hydrocarbon moiety having three or six carbon atoms.
xe2x80x9cAralkylxe2x80x9d means a moiety of the formula xe2x80x94Raxe2x80x94Rb, where Ra is alkyl and Rb is aryl as defined herein.
xe2x80x9cArylxe2x80x9d means a monocyclic or bicyclic aroma tic hydrocarbon moiety. In addition, one or more, preferably one, two or three, hydrogen atoms of the aryl moiety can be replaced by halo, nitro, cyano, hydroxy, amino, alkyl or alkoxy. Exemplary aryl groups include phenyl and naphthalenyl which can be substituted with one or more substituents listed above. Preferably, aryl is phenyl.
xe2x80x9cCycloalkylxe2x80x9d means a fully saturated cyclic hydrocarbon moiety of three to six ring carbon atoms, e.g., cyclopropyl, cyclopentyl and the like.
xe2x80x9cEsterxe2x80x9d refers to a compound comprising a moiety of the formula xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Rxe2x80x2, where Rxe2x80x2 is alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
xe2x80x9cHaloalkylxe2x80x9d refers to an alkyl moiety, as defined above, in which one or more hydrogen atoms attached to the carbon backbone have been replaced with one or more halides. Preferred halide is fluoride.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl moiety as defined herein having one or more, preferably one, two or three, substituents selected from xe2x80x94NRaRb, xe2x80x94ORc wherein Ra, Rb and Rc are independently of each other hydrogen, alkyl, or the corresponding protecting group.
xe2x80x9cHeteroaralkylxe2x80x9d means a moiety of the formula xe2x80x94Raxe2x80x94Rb, where Ra is alkyl and Rb is heteroaryl as defined herein.
xe2x80x9cHeteroarylxe2x80x9d means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. In addition, one or more, preferably one, two or three, hydrogen atoms of the heteroaryl moiety can be replaced by the substituents described above for the aryl group.
The terms xe2x80x9chydroxy protecting groupxe2x80x9d and xe2x80x9cother hydroxy protecting groupxe2x80x9d are used interchangeably herein and refer to hydroxy protecting groups known to one skilled in the art excluding alkyl or acyl groups, which are referred herein specifically. Representative hydroxy protecting groups include silyl ethers, carbonates, carbamates, substituted methyl ethers, substituted ethyl ethers, and the like. A list of other suitable hydroxy protecting groups can be found, for example, in Protective Groups in Organic Synthesis, 3rd edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, New York, 1999, which is incorporated herein by reference in its entirety.
xe2x80x9cPharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. xe2x80x9cA pharmaceutically acceptable excipientxe2x80x9d as used in the specification and claims includes both one and more than one such excipient.
xe2x80x9cTherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating or preventing a disease, is sufficient to effect such treatment or prevention for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
When referring to a chemical reaction, the terms xe2x80x9ctreatingxe2x80x9d, xe2x80x9ccontactingxe2x80x9d and xe2x80x9creactingxe2x80x9d are used interchangeably herein and refer to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
As used herein, the terms xe2x80x9cthose defined abovexe2x80x9d and xe2x80x9cthose defined hereinxe2x80x9d when referring to a variable incorporates by reference the broad definition of the variable as well as preferred, more preferred and most preferred definitions, if any.
One aspect of the present invention provides a 3-desoxy-20-desmethyl-20-cyclopropyl vitamin D3 analog ester of the formula: 
or a salt thereof,
wherein
dotted line is optionally a double bond;
L is a linker selected from the group consisting of:
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94, and
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
each of R2 and R3 is independently alkyl or haloalkyl; or R2 and R3 and together with the carbon atom to which they are attached to form a cycloalkyl; and
each of R1 and R4 is independently hydrogen, alkyl, acyl group or other hydroxy protecting group, provided at least one of R1 and R4 is an acyl group.
It has been surprisingly discovered that compounds of Formula I, where at least one of R1 and R4 is an acyl group are unexpectedly stable and crystalline relative to the compound where both of R1 and R4 are hydrogen, i.e., the parent diol.
When the cyclopentane ring moiety of Formula I does not contain a double bond, i.e., when the dotted line is absent, the stereochemistry of the side chain on the cyclopentane ring system can be alpha or beta. Preferably, the stereochemistry of the side chain on the cyclopentane ring system is beta, i.e., of the formula: 
In one particular embodiment of the present invention, the 3-desoxy vitamin D3 analog ester is of the formula: 
where R1, R2, R3, R4 and L are those defined herein.
In still another embodiment, the linker L is selected from the group consisting of xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94; xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94; xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94; and, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94. Preferably, L is xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94. More preferably L is xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94 where the double bond is trans.
Yet in another embodiment, R1 is preferably an acyl group, more preferably acetyl.
Still in another embodiment, R1 is an acyl group and R4is hydrogen or an acyl group.
In another embodiment, R1 is an acyl group and each of R2 and R3 is independently selected from the group consisting of methyl, ethyl and trifluoromethyl.
In yet another embodiment, R2 and R3 are alkyl or haloalkyl, preferably methyl or trifluoromethyl, most preferably trifluoromethyl.
A number of different substituent preferences have been given above and following any of these substituent preferences results in a compound of the invention that is more preferred than one in which the particular substituent preference is not followed. However, these substituent preferences are generally independent, although some preferences are mutually exclusive, and following more than one of these preferences may result in a more preferred compound than one in which fewer of the substituent preferences are followed.
While a variety of synthetic methodologies are available for preparation of compounds of Formula I, one particular embodiment for preparing compounds of Formula I includes coupling a ketone with a phosphine oxide. Specifically, compounds of Formula I can be prepared by contacting a compound of Formula II, 
with a phosphine oxide compound of the formula: 
under conditions sufficient to produce the compound of Formula I, wherein
each of Ar1 and Ar2 is independently optionally substituted aryl;
dotted line is optionally a double bond;
L is a linker selected from the group consisting of:
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94, and
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
each of R2 and R3 is independently alkyl or haloalkyl; or R2 and R3 and together with the carbon atom to which they are attached to form a cycloalkyl; and
each of R1 and R4 is independently alkyl, an acyl group or a hydroxy protecting group, and
(b) when neither R1 nor R4 is an acyl group, acylating the compound of Formula I with an acylating agent under conditions sufficient to produce a Compound of Formula I where at least one of R1 and R4 is an acyl group.
In one embodiment, R1 and R4 are hydroxy protecting groups. In this particular embodiment, the acylating step (b) comprises:
(i) removing the hydroxy groups by contacting the resulting compound of said step (a) with a hydroxy protecting group removing compound under conditions sufficient to produce a 1-hydroxy-3-desoxy vitamin D3 analog of the formula: 
xe2x80x83and
(ii) contacting the 1-hydroxy-3-desoxy vitamin D3 analog with an acylating agent under conditions sufficient to produce a 3-desoxy vitamin D3 analog ester of the Formula: 
xe2x80x83wherein R1a is an acyl group and R4a is hydrogen or an acyl group.
In another embodiment, R4a is an acyl group.
In yet another embodiment, Ar1 and Ar2 are phenyl.
Suitably hydroxy protecting groups are well known to one of ordinary skill in the art and examples of such hydroxy protecting groups are disclosed in Protective Groups in Organic Synthesis, 3rd edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, New York, 1999, and Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996), which are incorporated herein by reference in their entirety. Representative hydroxy protecting groups include benzyl and trityl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, carbamates and allyl ethers.
Typically, hydroxy groups are protected as silyl ethers; however, the scope of the invention includes the use of alternative hydroxyl protecting groups known in the art as described in the above disclosed Protective Groups in Organic Synthesis, 3rd edition, and Compendium of Synthetic Organic Methods, Vols. 1-8.
In general, a phosphine oxide of Formula III in tetrahydrofuran is reacted with n-butyllithium typically at about xe2x88x9278xc2x0 C. To this mixture is then added solution of a ketone of Formula II in tetrahydrofuran to provide a compound of Formula I. As stated above, when R1 and/or R4 are hydrogen, they are protected with hydroxy protecting groups prior to the coupling reaction. In such a case, the hydroxy protecting groups are then removed to provide a compound of Formula I.
Synthesis and purification of compounds of Formula III are known and conventional in this art. See, for example, M. R. Uskokovic et al. xe2x80x9cVitamin D Gene Regulation, Structure Function Analysis and Clinical Application,xe2x80x9d Paris, France, pp 139-145 (1991), U.S. Pat. No. 5,086,191 and U.S. Pat. No. 5,616,759 to DeLuca et al., U.S. Pat. No. 5,087,619 to Baggiolini et al., U.S. Pat. No. 5,384,314 to Doran et al., U.S. Pat. No. 5,428,029 to Doran et al., U.S. Pat. No. 5,451,574 to Baggiolini et al.; European patent publication EP 0 808,832 A2, patent publication WO 96/31216 to Brasitus et al.; Shiuey et al., J. Org. Chem., 55:243-247 (1990), Kiegel, J. et al. and Tetr. Lett., 32:6057-6060 (1991), Perlman, K. L., et al., Tetr. Lett., 32:7663-7666 (1991).
Reaction Scheme 1 illustrates a synthetic method for preparing a compound of Formula IA. 
In Reaction Scheme 1, the compound of Formula IV is a known compound prepared by the method described in W099/12894, published Mar. 18, 1999 (Preparation of 1,3-dihydroxy-20,20-dialkyl vitamin D3 analogs). The compound of Formula IV is converted to the compound of Formula V by selective partial reduction of the triple bond to anb E-double bond using lithium aluminum hydride in inert organic acid such as tetrahydrofuran. The reaction is typically conducted by adding the compound of Formula IV to a suspension of LiAlH4 in THF at 0xc2x0 C. or 5xc2x0 C. The reaction mixture is heated under refluxing condition to provide the compound of Formula V. The compound of Formula V is converted to the ketone of Formula VI by oxidation using an oxidizing agent such as pyridinium dichromate. The reaction is generally conducted in a halogenated solvent such as methylene chloride at room temperature. The hydroxy group of compound of Formula VI is then protected as a: silyl ether of Formula VII using a silylating agent, such as 1-(trimethylsilyl)imidazole, trimethylsilyl chloride or trimethylsilyl triflate, in an inert solvent, such as a halogenated solvent (e.g., methylene chloride), at room temperature. The compound of Formula IIIA is reacted with n-butyllithium and the resulting compound is reacted with the compound of Formula VII in tetrahydrofuran at temperature of generally about xe2x88x9278xc2x0 C., and the silyl protecting groups are then removed, for example, with tetrabutylammonium fluoride in tetrahydrofuran solvent to give the compound of Formula IAxe2x80x2. The free hydroxyl groups are then acetylated to provide the compound of Formula IA, for example, with acetic anhydride in pyridine. Because the secondary hydroxyl group is generally more reactive, it can be selectively acetylated depending on the amount of acetylating agent used and/or the reaction conditions used, e.g., the reaction temperature and/or the reaction time. Alternatively, both the secondary and the tertiary hydroxyl groups can be acteylated by using an excess amount of the acetylating agent and longer reaction time.
Similarly, a Z-stereoisomer analog or a saturated carbon chain analog of compound of Formula IA can be prepared by reduction of the compound of Formula IV with hydrogen in the presence of an appropriate hydrogenation catalyst, such as Pdxe2x80x94S or Pd, respectively. The resulting compounds can be subjected to similar reaction conditions as shown in Scheme I to produce the corresponding a Z-isomer analog and a saturated carbon chain analog of the compound of Formula IA.
As shown in Reaction Scheme II, a compound of Formula II comprising an acetylenic alcohol and varying alkyl, haloalkyl and cycloalkyl groups of R2 and R3 can be prepared by condensing an acetylide anion derived from a compound of Formula VIII (where Pg is a hydroxy protecting group) with an appropriate ketone, haloketone (e.g. hexafluoroacetone) and cycloketone, and removing the protecting group. 
The compound of Formula X is then subjected to a similar reaction conditions shown above in Reaction Scheme I (i.e., oxidation, protection and coupling) to produce a compound of Formula I having an acetylenic linker moiety.
In certain preferred embodiments, the dotted line is a double bond, i.e., a compound of the formula: 
In yet another preferred embodiment, the linker L is selected from the group consisting of:
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94;
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94;
xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94; and
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94.
Preferably, R1 is an acyl group.
Preferably, R4 is hydrogen or an acyl group.
Preferably, each of R2 and R3is independently selected from the group consisting of methyl, ethyl and trifluoromethyl or R2 and R3 together with the carbon atom to which they are attached to form a cyclopentyl ring.
A number of different substituent preferences have been given above and following any of these substituent preferences results in a compound of the invention that is more preferred than one in which the particular substituent preference, is not followed. However, these substituent preferences are generally independent, although some preferences are mutually exclusive, and following more than one of these preferences may result in a more preferred compound than one in which fewer of the substituent preferences are followed.
Another aspect of the invention provides salts of a compound of Formula I.
The compounds of the present invention are useful for the prevention and treatment of a variety of mammalian conditions manifested by loss of bone mass. All such conditions are referred to as xe2x80x9cbone-related diseasesxe2x80x9d and are described in more detail hereunder. In particular, the compounds of this invention are indicated for the prophylaxis and therapeutic treatment of osteoporosis and osteopenia in mammals without inducing hypercalciuria, hypercalcemia, or nephrotoxicity. xe2x80x9cHypercalcemiaxe2x80x9d is an excessive concentration of calcium in the serum; in humans (and rats) this corresponds to greater than about 10.5 mg/dl. xe2x80x9cIntolerable hypercalcemiaxe2x80x9d, usually occurring at serum calcium concentrations greater than about 12 mg/dl, is associated with emotional lability, confusion, delirium, psychosis, stupor, and coma.
The compounds of the present invention are useful in the treatment of Type I (postmenopausal), Type II (iatrogenic), and Type III (senile) osteoporosis, including that associated with corticosteroid treatment (e.g. for asthma), as well in the treatment of osteodystrophy due to renal dialysis and hyperparathyroidism. Treatment with the vitamin D3 analogs as described herein results in increased bone mineral density and unlike conventional treatments provides bone of good quality. Therefore, the treatments described herein may reduce the incidence of fracture and result in faster healing of pre-existing fractures. Such treatments are particularly useful for patients suffering from estrogen withdrawal (e.g. elderly females) who would otherwise be at risk for an increased fracture rate. Types of fractures treatable include both traumatic and osteoporotic fractures, e.g., fractures of the hip, neck of the femur, wrist, vertebrae, spine, ribs, sternum, larynx and trachea, radius/ulna, tibia, patella, clavicle, pelvis, humerus, lower leg, fingers and toes, face and ankle.
The compounds of the present invention are also useful in treating diseases caused by elevated levels of parathyroid hormone. In one aspect, compounds of the invention are used in treating secondary hyperparathyroidism associated with renal failure and in particular with reversing or reducing the bone loss associated with renal insufficiency. Other aspects include the treatment of renal osteodystrophy associated with late stage secondary hyperparathyroidism. Other aspects include the treatment of primary hyperparathyroidism.
Compounds of Formula I are also useful in treating neoplastic diseases such as leukemia, colon cancer, breast cancer and prostate cancer.
Generally, compounds of the present invention do not cause the elevated calcium levels observed with other vitamin D3 analogs such as 1,25 (OH)2 vitamin D3, thus providing an improved therapeutic ratio and better treatment of the above diseases.
In general, the compound of this invention may be administered in amounts between about 0.0002 and 0.5 mg compound/kg body weight per day, preferably from about 0.001 to about 0.1 mg/kg body weight per day, more preferably from about 0.002 to about 0.02 mg/kg body weight per day, most preferably from about 0.005 to about 0.010 mg/kg body weight per day. For a 50 kg human subject, the daily dose of active ingredient may be from about 0.01 to about 25 xcexcgs, preferably from about 0.05 to about 10 xcexcgs, most preferably from about 1.0 xcexcg to about 10 xcexcg per day. This dosage can be delivered in a conventional pharmaceutical composition by a single administration, by multiple applications, or via controlled release, as needed to achieve the most effective results, preferably once or twice daily by mouth. In certain situations, alternate day dosing can prove adequate to achieve the desired therapeutic response.
The selection of the exact dose and composition and the most appropriate delivery regimen are influenced by, inter alia, the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient. In general, the requisite dose is greater for higher doses of corticosteroids in the treatment of corticosteroid induced osteopenia.
Representative delivery regimens include oral,; parenteral (including subcutaneous, intramuscular and intravenous), rectal, buccal (including sublingual), pulmonary, transdermal, and intranasal, most preferably oral. Administration can be continuous or intermittent (e.g., by bolus injection).
A related aspect of this invention relates to combination therapies of compounds of Formula I with other active agents such as bisphosphonates, estrogen, SERMS (selective estrogen receptor modulators), calcitonins or anabolic therapies. Examples of bisphosphonates include alendronate, ibandronate, pamidronate, etidronate and risedronate. Examples of SERMS include raloxifene, dihydroraloxifene and lasofoxifene. Calcitonins include human and salmon calcitonin. Anabolic agents include parathyroid hormones (PTH) e.g. hPTH(1-34), PTH(1-84), and parathyroid hormone-related protein (PTHrP) and analogs thereof. Particular analogs of PTHrP are described in xe2x80x9cMono- and Bicyclic Analogs of Parathyroid Hormone-Related Protein. 1. Synthesis and Biological Studies,xe2x80x9d Michael Chorev et al. Biochemistry, 36:3293-3299 (1997) and xe2x80x9cCyclic analogs of PTH and PTHrP,xe2x80x9d WO 96/40193 and U.S. Pat. No. 5,589,452 and WO 97/07815. The other active agent may be administered concurrently, prior to or after the compound of Formula I and may be administered by a different delivery method.
A further aspect of the present invention relates to pharmaceutical compositions comprising a compound of the present invention as an active ingredient in admixture with a pharmaceutically acceptable non-toxic carrier. As mentioned above, such compositions can be prepared for parenteral (subcutaneous, intramuscular or intravenous) administration, particularly in the form of liquid solutions or suspensions; for oral or buccal administration, particularly in the form of tablets or capsules; for pulmonary or intranasal administration, particularly in the form of powders, nasal drops or aerosols; and for rectal or transdermal administration.
The compositions of the present invention can conveniently be administered in unit dosage form and can be prepared by any of the methods well-known in the pharmaceutical art, for example, as described in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa. (1985). Formulations for parenteral administration can contain as excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Formulations for nasal administration can be solid and can contain excipients, for example, lactose or dextran, or can be aqueous or oily solutions for use in the form of nasal drops or metered spray. For buccal administration typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
Orally administrable compositions can comprise one or more physiologically compatible carriers and/or excipients and can be in solid or liquid form. Tablets and capsules can be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrollidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulfate. Liquid compositions can contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethylcellulose, or edible fats; emulsifying agents such as lecithin, or acacia; vegetable oils such as almond oil, coconut oil, cod liver oil;, or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). Liquid compositions can be encapsulated in, for example, gelatin to provide a unit dosage form.
Preferred solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. SEG capsules are of particular interest because they provide distinct advantages over the other two forms (see Seager, H., xe2x80x9cSoft gelatin capsules: a solution to many tableting problemsxe2x80x9d; Pharmaceutical Technology, 9, (1985). Some of the advantages of using SEG capsules are: a) dose-content uniformity is optimized in SEG capsules because the drug is dissolved or dispersed in a liquid that can be dosed into the capsules accurately, b) drugs formulated as SEG capsules show good bioavailability because the drug is dissolved, solubilized or dispersed in an aqueous-miscible or oily liquid and therefore when released in the body the solutions dissolve or are emulsified to produce drug dispersions of high surface area, and c) degradation of drugs that are sensitive to oxidation during long-term storage is prevented because the dry shell of soft gelatin provides a barrier against the diffusion of oxygen.
The dry shell formulation typically comprises of about 40% to 60% concentration of gelatin, about a 20% to 30% concentration of plasticizer (such as glycerin, sorbitol or propylene glycol) and about a 30 to 40% concentration of water. Other materials such as preservatives, dyes, opacifiers and flavours also can be present. The liquid fill material comprises a solid drug that has been dissolved, solubilized or dispersed (with suspending agents such as beeswax, hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug in vehicles or combinations of vehicles such as mineral oil, vegetable oils, triglycerides, glycols, polyols and surface-active agents.